Methods of producing anamorelin hydrochloride having controlled chloride content

ABSTRACT

The present invention relates to particulate forms of anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride having controlled chloride content, preferably isolated in an amorphous and/or fine particulate state, processes for making the particulate forms, and pharmaceutical compositions comprising the particulate forms.

FIELD OF THE INVENTION

The present invention relates to anamorelin hydrochloride, improvedforms of anamorelin hydrochloride having reduced impurities andcontrolled chloride content, and improved processes for making and usinganamorelin hydrochloride.

BACKGROUND OF THE INVENTION

Growth hormone is a major participant in the control of several complexphysiologic processes including growth and metabolism. Growth hormone isknown to have a number of effects on metabolic processes such asstimulating protein synthesis and mobilizing free fatty acids, andcausing a switch in energy metabolism from carbohydrate to fatty acidmetabolism. Deficiencies in growth hormone can result in dwarfism andother severe medical disorders.

The release of growth hormone from the pituitary gland is controlleddirectly and indirectly by a number of hormones and neurotransmitters.Growth hormone release can be stimulated by growth hormone releasinghormone (GHRH) and inhibited by somatostatin.

The use of certain compounds to increase levels of growth hormone inmammals has previously been proposed. Anamorelin is one such compound.Anamorelin is a synthetic orally active compound originally synthesizedin the 1990s as a growth hormone secretagogue for the treatment ofcancer related cachexia. The free base of anamorelin is chemicallydefined as:

-   (3R)1-(2-methylalanyl-D-tryptophyl)-3-(phenylmethyl)-3-piperidinecarboxylic    acid 1,2,2trimethylhydrazide,-   3-{(2R)-3-{(3R)-3-benzyl-3-[(trimethylhydrazino)carbonyl]piperidin-1-yl}-2-[(2-met    hylalanyl)amino]-3-oxopropyl}-1H-indole, or-   2-Amino-N-[(1R)-2-[(3R)-3-benzyl-3-(N,N′,N′-trimethylhydrazino-carbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide    and has the below chemical structure:

U.S. Pat. No. 6,576,648 to Ankerson reports a process of preparinganamorelin as the fumarate salt, with the hydrochloride salt produced asan intermediate in Step (j) of Example 1. U.S. Pat. No. 7,825,138 toLorimer describes a process for preparing crystal forms of the free baseof anamorelin.

There is a need to develop anamorelin monohydrochloride as an activepharmaceutical ingredient with reduced impurities and improved stabilityover prior art forms of anamorelin hydrochloride, such as thosedescribed in U.S. Pat. No. 6,576,648, having good solubility,bioavailability and processability. There is also a need to developmethods of producing pharmaceutically acceptable forms of anamorelinmonohydrochloride that have improved yield over prior art processes,reduced residual solvents, and controlled distribution of chloridecontent.

SUMMARY OF THE INVENTION

It has unexpectedly been discovered that the process of making thehydrochloride salt of anamorelin described in Step (j) of U.S. Pat. No.6,576,648 can result in excessive levels of chloride in the finalproduct, and that this excess chloride leads to the long-terminstability of the final product due at least partially to an increasein the amount of the less stable dihydrochloride salt of anamorelin.Conversely, because anamorelin free base is less soluble in water thanthe hydrochloride salt, deficient chloride content in the final productcan lead to decreased solubility of the molecule. The process describedin U.S. Pat. No. 6,576,648 also yields a final product that containsmore than 5000 ppm (0.5%) of residual solvents, which renders theproduct less desirable from a pharmaceutical standpoint, as described inICH Harmonized Tripartite Guideline. See Impurities: Guideline forresidual solvents Q3C(R3).

In order to overcome these problems, methods have been developed which,for the first time, allow for the efficient and precise control of thereaction between anamorelin free base and hydrochloric acid in situ,thereby increasing the yield of anamorelin monohydrochloride from thereaction and reducing the incidence of unwanted anamorelindihydrochloride. According to the method, the free base of anamorelin isdissolved in an organic solvent and combined with water and hydrochloricacid, with the molar ratio of anamorelin and chloride tightly controlledto prevent an excess of chloride in the final product. The water andhydrochloric acid can be added either sequentially or at the same timeas long as two separate phases are formed. Without wishing to be boundby any theory, it is believed that as the anamorelin free base in theorganic phase is protonated by the hydrochloric acid it migrates intothe aqueous phase. The controlled ratio of anamorelin free base andhydrochloric acid and homogenous distribution in the aqueous phaseallows for the controlled formation of the monohydrochloride salt overthe dihydrochloride, and the controlled distribution of the resultingchloride levels within individual batches and among multiple batches ofanamorelin monohydrochloride.

Thus, in a first embodiment the invention provides methods for preparinganamorelin monohydrochloride or a composition comprising anamorelinmonohydrochloride comprising: (a) dissolving anamorelin free base in anorganic solvent to form a solution; (b) mixing said solution with waterand hydrochloric acid for a time sufficient to: (i) react saidanamorelin free base with said hydrochloric acid, and (ii) form anorganic phase and an aqueous phase; (c) separating the aqueous phasefrom the organic phase; and (d) isolating anamorelin monohydrochloridefrom the aqueous phase.

In a particularly preferred embodiment, the molar ratio of anamorelin tohydrochloric acid used in the process is less than or equal to 1:1, soas to reduce the production of anamorelin dihydrochloride and otherunwanted chemical species. Thus, for example, hydrochloric acid can beadded at a molar ratio of from 0.90 to 1.0 relative to said anamorelin,from 0.90 to 0.99, or from 0.93 to 0.97.

In another particularly preferred embodiment, the anamorelinmonohydrochloride or a composition comprising anamorelinmonohydrochloride is isolated from the aqueous phase via spray drying,preferably preceded by distillation. This technique has provenespecially useful in the manufacture of anamorelin monohydrochloride ora composition comprising anamorelin monohydrochloride because of theexcellent reduction in solvent levels observed, and the production of astable amorphous form of anamorelin monohydrochloride or a compositioncomprising anamorelin monohydrochloride.

In other embodiments, the invention relates to the various forms ofanamorelin monohydrochloride and compositions comprising anamorelinmonohydrochloride produced by the methods of the present invention. In afirst embodiment, which derives from the controlled chloride contentamong batches accomplished by the present methods, the inventionprovides anamorelin monohydrochloride or a composition comprisinganamorelin monohydrochloride having an inter-batch chloride content offrom 5.8 to 6.2%, preferably from 5.8 to less than 6.2%. Alternatively,the invention provides anamorelin monohydrochloride or a compositioncomprising anamorelin monohydrochloride having a molar ratio of chlorideto anamorelin less than or equal to 1:1, such as from 0.9 to 1.0 or0.99. In yet another embodiment the invention provides an amorphous formof anamorelin monohydrochloride or a composition comprising anamorelinmonohydrochloride. Further descriptions of the anamorelinmonohydrochloride and compositions comprising the anamorelinmonohydrochloride are given in the detailed description which follows.

Additional embodiments and advantages of the invention will be set forthin part in the description which follows, and in part will be obviousfrom the description, or may be learned by practice of the invention.The embodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims. It is to be understood that both theforegoing general description and the following detailed description areexemplary and explanatory only and are not restrictive of the invention,as claimed.

That is, the present invention relates to:

[Par. 1] Anamorelin monohydrochloride having a chloride content rangingfrom 5.8 to 6.2%.

[Par. 2] Anamorelin monohydrochloride comprising a chloride:anamorelinmolar ratio of from 0.9 to 0.99.

[Par. 3] Anamorelin monohydrochloride in an amorphous state.

[Par. 4] The anamorelin monohydrochloride of Par. 1, 2 or 3, in anisolated state.

[Par. 5] The anamorelin monohydrochloride of Par. 1, 2 or 3, comprisingless than 0.5% impurities.

[Par. 6] The anamorelin monohydrochloride of Par. 1, 2 or 3, comprisingfrom 1 to 3% water.

[Par. 7] The anamorelin monohydrochloride of Par. 5, wherein theimpurities are selected from by-products, contaminants, degradationproducts and residual solvents.

[Par. 8] The anamorelin monohydrochloride of Par. 7, comprising aresidual solvent selected from methanol, butyl acetate, propyl acetate,ethyl acetate, isopropyl acetate, isobutyl acetate, methyl acetate,methylethyl ketone, methylisobutyl ketone, 2-methyltetrahydrofuran andcombinations thereof in an amount less than 1000 ppm.

[Par. 9] The anamorelin monohydrochloride of Par. 8, wherein theresidual solvent is isopropyl acetate.

[Par. 10] The anamorelin monohydrochloride of Par. 1, 2 or 3, having apurity greater than 99%.

[Par. 11] Anamorelin monohydrochloride having a purity greater than 99%and a chloride content of from 5.8 to 6.2%, comprising less than 0.5%residual solvent.

[Par. 12] A composition comprising anamorelin monohydrochloride, whereinthe composition comprises a chloride content of from 5.8 to 6.2%.

[Par. 13] A composition comprising anamorelin monohydrochloride whereinthe composition comprises a chloride:anamorelin molar ratio of from 0.9to 0.99.

[Par. 14] The composition of Par. 12 or 13, in the substantial absenceof anamorelin hydrochloride other than anamorelin monohydrochloride.

[Par. 15] The composition of Par. 12, 13 or 14, in an amorphous state.

[Par. 16] The composition of Par. 12, 13, 14 or 15, in an isolatedstate.

[Par. 17] The composition of Par. 12, 13, 14 or 15, comprising less than0.5% impurities.

[Par. 18] The composition of Par. 12, 13, 14 or 15, comprising from 1 to3% water.

[Par. 19] The composition of Par. 17, wherein the impurities areselected from by-products, contaminants, degradation products andresidual solvents.

[Par. 20] The composition of Par. 19, comprising a residual solventselected from methanol, butyl acetate, propyl acetate, ethyl acetate,isopropyl acetate, isobutyl acetate, methyl acetate, methylethyl ketone,methylisobutyl ketone, 2-methyltetrahydrofuran and combinations thereofin an amount less than 1000 ppm.

[Par. 21] A composition comprising anamorelin monohydrochloride in thesubstantial absence of anamorelin hydrochloride other than anamorelinmonohydrochloride, having a chloride content of from 5.8 to 6.2%, lessthan 0.5% residual solvent, and a purity greater than 99%.

[Par. 22] A process for preparing anamorelin monohydrochloridecomprising:

-   -   a) dissolving anamorelin free base in an organic solvent to form        a solution;    -   b) mixing said solution with water and hydrochloric acid for a        time sufficient to:        -   i) react said anamorelin free base with said hydrochloric            acid, and        -   ii) form an organic phase and an aqueous phase;    -   c) separating the aqueous phase from the organic phase; and    -   d) isolating said anamorelin monohydrochloride from said aqueous        phase.

[Par. 23] The process of Par. 22, wherein said water and hydrochloricacid in step b are added sequentially or concurrently to said solution.

[Par. 24] The process of Par. 23, wherein said organic solvent isselected from butyl acetate, propyl acetate, ethyl acetate, isopropylacetate, isobutyl acetate, methyl acetate, methylethyl ketone,methylisobutyl ketone, 2-methyltetrahydrofuran, and combinationsthereof.

[Par. 25] The process of Par. 24, wherein said organic solvent isisopropyl acetate.

[Par. 26] The process of Par. 22, wherein the anamorelinmonohydrochloride is isolated from said aqueous phase by spray drying.

[Par. 27] The process of Par. 22, wherein said anamorelinmonohydrochloride is combined with from 0.9 to 1.0 molar equivalents ofhydrochloric acid.

[Par. 28] The process of Par. 22, further comprising processing theanamorelin monohydrochloride into a finished dosage form.

[Par. 29] Anamorelin monohydrochloride produced by the method of Par.22.

[Par. 30] A pharmaceutical composition comprising:

-   -   a) a therapeutically effective amount of the anamorelin        monohydrochloride of Par. 1, 2, 3 or 29, or the composition of        Par. 12; and    -   b) one or more pharmaceutically acceptable excipients.

[Par. 31] A method of making a pharmaceutical dosage form comprising:

-   -   a) combining a therapeutically effective amount of the        anamorelin monohydrochloride of Par. 1, 2, 3, or 29, or the        composition of Par. 12, with one or more pharmaceutically        acceptable excipients to form a mixture; and    -   b) processing said mixture into a finished dosage form.

Additional embodiments and advantages of the invention will be set forthin part in the description which follows, and in part will be obviousfrom the description, or may be learned by practice of the invention.The embodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims. It is to be understood that both theforegoing general description and the following detailed description areexemplary and explanatory only and are not restrictive of the invention,as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray powder diffraction pattern of amorphous anamorelinmonohydrochloride or a composition comprising amorphous anamorelinmonohydrochloride prepared according to the methods of the presentinvention.

FIG. 2 is an infrared spectrum in KBr of amorphous anamorelinmonohydrochloride or a composition comprising amorphous anamorelinmonohydrochloride prepared according to the methods of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of preferred embodiments of the inventionand the Examples included therein.

DEFINITIONS AND USE OF TERMS

“A,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an ingredient”includes mixtures of ingredients, reference to “an active pharmaceuticalagent” includes more than one active pharmaceutical agent, and the like.

“Comprise,” or variations such as “comprises” or “comprising,” will beunderstood to imply the inclusion of a stated element, integer or step,or group of elements, integers or steps, but not the exclusion of anyother element, integer or step, or group of elements, integers or steps.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

All percentages and parts (i.e. ppm) expressed herein are stated on aweight basis unless specifically stated otherwise.

Unless otherwise specified herein, it will be understood that allnumeric values and ranges could be qualified by the term “about” or“approximately” to accommodate the degree of imprecision or variabilityallowed in the pharmaceutical industry for manufacturing imprecision,degradation over time, and generic equivalence. Unless otherwiseindicated, variability of +/10% is allowed and intended for any numericfigure or range given in this application, and is meant by the term“about” or “approximately.”

“Impurity” refers to any chemical in a pharmaceutical ingredient otherthan anamorelin monohydrochloride as the ingredient itself and water.Impurities thus include reaction by-products, contaminants, degradationproducts, and residual solvents such as organic volatile impurities.

“Residual solvent” refers to any organic solvent which is used inpreparing anamorelin monohydrochloride.

“Isolated” refers to a state suitable for use as an activepharmaceutical ingredient in solid form, prior to admixing with anypharmaceutically acceptable excipients. Thus, the term generallyrequires that the recited ingredient be present as an isolated solidmaterial to the exclusion of any pharmaceutically acceptable excipients,and preferably having less than 10, 5, 3, 1, or 0.5% impurities.

“Anamorelin monohydrochloride” refers to the salt form of anamorelincomprising a precise 1:1 stoichiometric ratio of anamorelin and HCl(i.e. 6.08 wt % Cl—). However, the anamorelin monohydrochloride may bepresent within a composition that does not have a precise 1:1 ratio ofanamorelin and HCl because, for example, the composition may containsmall quantities of anamorelin free base and/or anamorelin hydrochloride(e.g., anamorelin dihydrochloride) other than anamorelinmonohydrochloride which do not substantially affect the stability of thecomposition. Thus, expressed as a weight percentage of chloride content,“anamorelin monohydrochloride” or “a composition comprising anamorelinmonohydrochloride” may comprise from 5.6 to 6.3 wt %, and preferablyfrom 5.8 to 6.2 wt %, more preferably from 5.9 or 6.0 to 6.1 wt %chloride. The chloride content in the composition is calculated by theformula described in the Example 1. The “hydrochloride” salt ofanamorelin, in contrast, encompasses any molar ratio of anamorelin toHCl. “Anamorelin” is used herein to refer to the hydrochloride salt ofanamorelin as well as the free base, and should not be taken to mean thefree base unless stated so expressly.

“A composition comprising anamorelin monohydrochloride” refers to theactive pharmaceutical ingredient which comprises anamorelinmonohydrochloride and does not include any pharmaceutically acceptableexcipients. More concretely the term refers to the composition having achloride content ranging from 5.8 to 6.2%, preferably from 5.8 to 6.1%,in the substantial absence of anamorelin free base, anamorelinhydrochloride other than anamorelin monohydrochloride, and without anypharmaceutically acceptable excipients.

“Purity” refers to the converted value into anamorelin free base withinthe sample when anamorelin monohydrochloride or a composition comprisinganamorelin monohydrochloride prepared by the methods of presentinvention is measured via HPLC under the conditions described in Example3.

Methods of Production

As discussed above, the present invention provides methods of producinghigh-quality anamorelin monohydrochloride as an active pharmaceuticalingredient, as well as the product produced by such methods. Theanamorelin hydrochloride of the present invention is preferably referredto simply as anamorelin hydrochloride, but could also be considered acomposition comprising anamorelin monohydrochloride, due to the presenceof impurities and degradation products.

Thus, in one embodiment the present invention provides methods forpreparing anamorelin monohydrochloride or a composition comprisinganamorelin monohydrochloride having a controlled content anddistribution of chloride comprising: (a) dissolving anamorelin free basein an organic solvent to form a solution; (b) mixing said solution withwater and hydrochloric acid for a time sufficient to: (i) react saidanamorelin free base with said hydrochloric acid; and (ii) form anorganic phase and an aqueous phase; (c) separating the aqueous phasefrom the organic phase; and (d) isolating anamorelin monohydrochloridefrom the aqueous phase.

The organic solvent used to prepare the initial solution is preferablyone in which (i) anamorelin free base is more soluble than it is inwater (ii) anamorelin monohydrochloride is less soluble than it is inwater, (iii) the organic solvent has limited miscibility with water, and(iv) the organic solvent forms an azeotrope with water or has a lowerboiling point than water. Examples of suitable organic solvents for theanamorelin free base include but are not limited to butyl acetate,propyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate,methyl acetate, methylethyl ketone, methylisobutyl ketone and2-methyltetrahydrofuran, preferably isopropyl acetate.

The concentration of the hydrochloric acid solution is governedprimarily by the desired molar ratio of anamorelin and chloride in thefinal composition, which will dictate the number of moles ofhydrochloric acid in the aqueous phase. In a preferred embodiment, themolarity of the hydrochloric acid solution ranges from about 0.1 toabout 13 or from about 1.0 to about 10, and the volume of the solutionis determined by the molarity of the solution and the quantity ofanamorelin to be reacted. In various embodiments, the molar ratio ofchloride to anamorelin free base in the reaction vessel can range fromabout 0.85 to about 1.04, from about 0.92 to about 1.02, from about 0.92to about 1.00, or from about 0.93 to about 0.97.

Once the anamorelin with hydrochloric acid reaction is complete, theorganic phase can be separated from the aqueous phase by any suitablephase extraction technique, including physical extraction of one phasefrom the mixture or distillation. Distillation can be performed usingvarious means, such as simple distillation, fractional distillation,vacuum distillation and preferably azeotropic distillation. Thedistillation temperature is determined based upon the boiling point ofthe particular organic solvent(s) intended to be removed.

Once the aqueous phase has been separated from the organic phase, theanamorelin monohydrochloride or a composition comprising anamorelinmonohydrochloride can be isolated from the aqueous phase via knowntechniques, including settling, sedimentation and concentration.Concentration is the preferred method, particularly concentration viaspray drying, optionally in the presence of an inert gas.

Spray drying is a method of producing a dry powder from a liquid orslurry by rapidly drying with a hot gas. It is well suited for thecontinuous production of dry solids in either powder, granulate oragglomerate form from liquid feedstocks as solutions, emulsions andpumpable suspensions. Spray drying is an ideal process where theend-product must comply with precise quality standards regardingparticle size distribution, residual moisture content, bulk density,and/or particle shape.

Spray drying involves the atomization of a liquid feedstock into adroplet spray, and contacting the droplets with hot air in a dryingchamber. The spray is produced by either a rotary (wheel) or nozzleatomizer. Evaporation of moisture from the droplets and formation of dryparticles proceed under controlled temperature and airflow conditions.Powder is discharged continuously from the drying chamber. Operatingconditions and dryer design are selected according to the dryingcharacteristics of the product and powder specifications.

A spray dryer is a device used in spray drying. It takes a liquid streamand separates the solute or suspension from a liquid phase byevaporating the solvent. The solid is usually collected in a drum orcyclone. The liquid input stream is sprayed through a nozzle into a hotvapor stream and vaporized. Solids form as moisture quickly leaves thedroplets. A nozzle is usually used to make the droplets as small aspossible, maximizing heat transfer and the rate of water vaporization. Arepresentative spray dryer comprises a feed pump, atomizer, air heater,air disperser, drying chamber, and systems for exhaust air cleaning andpowder recovery. The selection of the atomizer, the most suitableairflow pattern, and the drying chamber design are determined by thedrying characteristics and quality requirements for the particularproduct.

The initial contact between spray droplets and drying air controlsevaporation rates and product temperatures in the dryer. There are threemodes of contact: 1) Co-current: Drying air and particles move throughthe drying chamber in the same direction; 2) Counter-current: Drying airand particles move through the drying chamber in opposite directions;and 3) Mixed flow: Particle movement through the drying chamberexperiences both co-current and counter-current phases.

Many commercially available spray dryers can be used in the spray dryingstep according to the present invention. A representative example is theMini-Spray Dryer (Model: Buchi 190, Switzerland), which operates in aco-current manner, i.e., the sprayed product and the drying gas flow inthe same direction. Other suitable spray dryers include the Niro MobileMinor (trade mark, GEA Process Engineering Inc.), Niro QSD-3.6 (trademark, GEA Process Engineering Inc.), L-8i (Ohkawara Kakoki Co., Ltd.)and so forth. The drying gas can be air or inert gases such as nitrogen,argon and carbon dioxide. The spray drying is preferably carried outwith the inlet gas temperature in the range of from about 180 to about200° C. and the outlet gas temperature in the range of from about 80 toabout 100° C. Preferred methods of spray drying the anamorelinhydrochloride are given in the examples hereto.

Anamorelin Monohydrochloride

Still other embodiments pertain to the novel forms of anamorelinmonohydrochloride or compositions comprising anamorelinmonohydrochloride produced by the present invention. For example, in afirst principal embodiment, the invention provides for anamorelinmonohydrochloride or compositions comprising anamorelinmonohydrochloride having a uniformly controlled chloride content amongbatches. In this embodiment the invention provides anamorelinmonohydrochloride having an inter-batch (i.e. batch-to-batch) chloridecontent that varies by no more than 7%, 5%, 3% or even 2%. For example,the invention may provide anamorelin monohydrochloride or a compositioncomprising anamorelin monohydrochloride having an inter-batch chloridecontent that ranges from 5.8 to 6.2%, 5.9 to 6.2%, 5.9 to 6.1%, or 6.0to 6.1%.

In a second principal embodiment, the invention provides anamorelinmonohydrochloride or a composition comprising anamorelinmonohydrochloride having a molar ratio of chloride to anamorelin of from0.92 to 1.02, or from 0.95 to 1.00. This ratio can exist throughout anentire batch, as an average of samples taken from the batch, or as oneor more samples within a batch.

A third principal embodiment provides anamorelin monohydrochloride or acomposition comprising anamorelin monohydrochloride in an amorphousstate. The amorphous state can be represented by an X-ray powderdiffraction pattern substantially as depicted in FIG. 1 or,alternatively or in addition, by the infrared resonance spectrumdepicted in FIG. 2.

The anamorelin monohydrochloride or a composition comprising anamorelinmonohydrochloride of each of the foregoing principal embodiments ispreferably highly soluble in water. For example, the solubility in waterof the anamorelin monohydrochloride or a composition comprisinganamorelin monohydrochloride is preferably greater than about 100 mg/ml.The anamorelin monohydrochloride or composition comprising anamorelinmonohydrochloride also preferably has a low residual solvent content.For example, the total organic volatile impurities such as methanol,isopropanol, isopropyl acetate, ethyl acetate or other organic solventsused in preparing the drug substance are preferably less than 5,000 ppm,3,000 ppm, or even 1,000 ppm. Alternatively or in addition, theanamorelin monohydrochloride or composition comprising anamorelinmonohydrochloride has a residual solvent content less than about 0.5%,0.3%, or even 0.1% based upon the total weight of the anamorelinmonohydrochloride or composition comprising anamorelinmonohydrochloride.

The anamorelin monohydrochloride or composition comprising anamorelinmonohydrochloride of each of the foregoing embodiments preferably hashigh purity and low impurities including residual solvents. For example,total impurities such as by-products, contaminants, degradation productsand residual solvents used in preparing the drug substance arepreferably less than 3%, 2%, 1%, or 0.5%. In other words, the anamorelinmonohydrochloride or composition comprising anamorelin monohydrochlorideis in a pharmaceutically acceptable form having greater than 97%, 98%,or even 99% purity.

Alternatively or in addition, the anamorelin monohydrochloride orcomposition comprising anamorelin monohydrochloride of each of theforegoing embodiments can be characterized by the weight percent ofchloride in the composition, or in a sample of the composition, and invarious embodiments the anamorelin monohydrochloride or compositioncomprising anamorelin monohydrochloride is defined by a chloride contentranging from about 5.8% to about 6.2%, and preferably from about 5.9% toabout 6.1% (or 6.08%). The anamorelin monohydrochloride or compositioncomprising anamorelin monohydrochloride can also be characterized by itswater content, alternatively or in addition to the other characteristicsof the compound, and in various embodiments the compounds of the presentinvention comprise less than 5, 4, 3 or 2% water.

Medical Uses

Because the anamorelin monohydrochloride or composition comprisinganamorelin monohydrochloride of the present invention has growth hormonesecretagogue activity, it is useful for preventing and/or treatingconditions which require increased plasma growth hormone levels, as ingrowth hormone deficient humans, elderly patients and livestock. Theanamorelin monohydrochloride or a composition comprising anamorelinmonohydrochloride is found particularly useful in the treatment ofcancer related cachexia.

Pharmaceutical Dosage Forms

The anamorelin monohydrochloride or composition comprising anamorelinmonohydrochloride of the present invention can be present in an isolatedstate or, alternatively, it can be formulated into a pharmaceuticaldosage form (i.e., pharmaceutical composition) that comprises atherapeutically effective amount of the compound and one or morepharmaceutically acceptable excipients. As used herein the language“pharmaceutically acceptable excipient” includes solvents, dispersionmedia, coatings, antibacterial and antifungal agents, tonicity agents,buffers, antioxidants, preservatives, absorption delaying agents, andthe like, compatible with pharmaceutical administration.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

A pharmaceutical composition is formulated to be compatible with itsintended route of administration. Examples of routes of administrationinclude parenteral, oral, transmucosal, and rectal administration. Thecompounds for use in the method of the invention can be formulated foradministration by any suitable route, such as for oral or parenteral,for example, transmucosal (e.g., sublingual, lingual, (trans)buccal,nasal, (trans)dermal, and (trans)rectal) administration.

Suitable compositions and dosage forms include tablets, capsules,caplets, pills, gel caps, troches, dispersions, suspensions, solutions,syrups, granules, beads, gels, powders, pellets, magmas, lozenges,discs, suppositories, liquid sprays, or dry powders.

It is preferred that the anamorelin monohydrochloride or the compositioncomprising anamorelin monohydrochloride be orally administered. Suitableoral dosage forms include, for example, tablets, capsules or capletsprepared by conventional means with pharmaceutically acceptableexcipients such as binding agents (e.g., polyvinylpyrrolidone orhydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., sodium starch glycolate); and/orwetting agents (e.g., sodium lauryl sulfate). If desired, the tabletscan be coated, e.g., to provide for ease of swallowing or to provide adelayed release of active ingredients, using suitable methods. Tabletsare typically formed by compression methods, whereas capsules are formedby filling a dry admixture into a hard outer shell.

Liquid preparations can be in the form of solutions, syrups orsuspensions, and are prepared by mixing the excipients along with theanamorelin hydrochloride in a suitable liquid medium such as water oralcohol. Liquid preparations (e.g., solutions, suspensions and syrups)suitable for oral administration can be prepared by conventional meanswith pharmaceutically acceptable additives such as suspending agents(e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl hydroxy benzoates or sorbic acid).

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary and arenot intended to limit the disclosure. Efforts have been made to ensureaccuracy with respect to numbers (e.g., amounts, temperature, etc.), butsome errors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

Example 1 Preparation of Anamorelin Hydrochloride

Various methods have been developed to prepare the hydrochloric acidsalt of anamorelin, with differing results.

In a first method, which is the preferred method of the presentinvention, anamorelin free base was carefully measured and dissolved inisopropyl acetate. Anamorelin free base was prepared according to knownmethod (e.g., U.S. Pat. No. 6,576,648). A fixed volume of HCl in watercontaining various molar ratios (0.80, 0.95, 1.00 or 1.05) of HClrelative to the anamorelin free base was then combined with theanamorelin/isopropyl acetate solution, to form a mixture having anorganic and an aqueous phase. The aqueous phase of the mixture wasseparated from the organic phase and the resulting aqueous phase wasconcentrated by spray drying to obtain the batches of anamorelinmonohydrochloride (or a composition comprising anamorelinmonohydrochloride) shown in Table 1A.

Approximately 150 mg of the resulting spray dried sample of anamorelinmonohydrochloride (or composition comprising anamorelinmonohydrochloride) was accurately weighed out and dissolved in methanol(50 mL). Acetic acid (5 mL) and distilled water (5 mL) were added to themixture. The resulting mixture was potentiometrically titrated using0.01N silver nitrate and the endpoint was determined. A blankdetermination was also performed and correction was made, if necessary.The chloride content in the sample was calculated by the followingformula. This measurement method of chloride content was performedwithout any cations other than proton (H⁺).

Chloride content (%)=V×N×35.453×100×100/{W×[100−(water content(%))−(residual solvent (%))]}

-   -   V: volume at the endpoint (mL)    -   N: actual normality of 0.01 mol/L silver nitrate    -   35.453: atomic weight of Chlorine    -   W: weight of sample (mg)

TABLE 1A HCl Chloride Content (equivalent) (wt. %) 0.80 5.7 0.95 5.91.00 6.0 1.05 6.3

This data showed that anamorelin monohydrochloride produced by a fixedvolume of HCl in water containing 0.80 or 1.05 molar equivalents of HClrelative to anamorelin free base had levels of chloride that wereundesirable, and associated with product instability as shown in Example3.

Alternatively, a fixed volume of HCl in water containing 0.95 moles ofHCl relative to anamorelin free base was used to prepare anamorelinmonohydrochloride (or composition comprising anamorelinmonohydrochloride) as follows. Anamorelin free base (18.8 g, 34.4 mmol)and isopropyl acetate (341.8 g) were mixed in a 1000 mL flask. Themixture was heated at 40±5° C. to confirm dissolution of the crystalsand then cooled at 25±5° C. Distilled water (22.3 g) and 3.6% dilutedhydrochloric acid (33.1 g, 32.7 mmol, 0.95 equivalents) were added intothe flask and washed with distilled water. After 30 minutes stirring,the reaction was static for more than 15 minutes and the lower layer(aqueous layer) was transferred into a separate 250 mL flask. Distilledwater was added to the flask and concentrated under pressure at 50±5° C.The resulting aqueous solution was then filtered and product isolated byspray drying to afford anamorelin monohydrochloride A (the presentinvention).

The physical properties of anamorelin monohydrochloride A were comparedto anamorelin monohydrochloride produced by a traditional comparativemethod (“anamorelin monohydrochloride B”) (comparative example).Anamorelin mono hydrochloride B in the comparative example was producedby bubbling HCl gas into isopropyl acetate to produce a 2M solution ofHCl, and reacting 0.95 molar equivalents of the 2M HCl in isopropylacetate with anamorelin free base. The physical properties of anamorelinmonohydrochloride B are reported in Table 1B. This data shows that when0.95 equivalents of HCl is added to anamorelin free base, the chloridecontent (or amount of anamorelin dihydrochloride) is increased, evenwhen a stoichiometric ratio of hydrochloride to anamorelin of less than1.0 is used, possibly due to uncontrolled precipitation. In addition,this data shows that the concentration of residual solvents inanamorelin monohydrochloride B was greater than the concentration inanamorelin monohydrochloride A.

TABLE 1B Anamorelin Chloride Residual Solvent HCl Content ConcentrationSalt/Properties HCl (wt. %) (ppm) A mono 5.9 <1,000 B mono 6.330,000-50,000A similar decrease in residual solvent concentration was observed when2-methyltetrahydrofuran was used as the dissolving solvent foranamorelin free base instead of isopropyl acetate in the process forpreparing spray dried anamorelin monohydrochloride A (data notreported).

The residual solvent (organic volatile impurities) concentration(specifically isopropyl acetate) of anamorelin monohydrochloride inTABLE 1B was measured using gas chromatography (GC-2010, ShimadzuCorporation) according to the conditions shown in TABLE 1C.

GAS CHROMATOGRAM CONDITIONS Detector Flame ionization detector ColumnDB624 (length 30 m, i.d. 0.32 mm, film thickness 1.8 μm, J&W) orequivalent Carrier gas Helium Flow rate 39 cm/sec(about 2.5 mL/min)Column temperature 40° C. (0-6 min) to (10° C./min) to 80° C. to (50°C./min) to 250° C. (13.425 min) Injection temperature 150° C. Detectortemperature 260° C. Make-up gas Nitrogen 40 mL/min Run duration  11 minHEAD SPACE CONDITIONS Oven temperature  80° C. Needle temperature 130°C. Transfer temperature 140° C. Equilibration time  20 min Pressurizedtime 1.0 min Drawing time 1.0 min Carrier gas pressure 159 kPa Injection time 0.08 min 

Example 2 Spray Dry Methods

Several spray dry methods have been developed by varying the type ofnozzle, the conditions at the nozzle, the inlet and outlet temperatures,the temperature of the condenser, and the feed rate. The amount ofanamorelin monohydrochloride (or composition comprising anamorelinmonohydrochloride) produced, the yield of each process andrepresentative process parameters according to the present inventionusing Niro QSD-3.6 (trade mark, GEA process engineering Inc.) arereported in Table 2A.

TABLE 2A Co-current nozzle Amount Ø Flow [kg/h]/ T inlet T outlet Tcondenser Feed rate of product Batch [mm] P [bar] [° C.] [° C.] [° C.][kg/h] [kg] Yield 1 2 25 190 95 2 13.5 6.15 92.5% 1.6 A 2 25 190 95 2 2549.85 94.6% 1.5 B 2 25 190 95 2 25 130.4 98.6% 1.6 Rotary nozzle PAmount Batch [bar] Flow [kg/h] T inlet T outlet T condenser Feed rate ofproduct Yield 2 3.3 10.1 190 95 2 13.5 6.12 98.5% 3 4.4 13.6 190 95 213.5 5.97 99.2% 4 5.0 15.6 190 95 2 13.5 6.39 97.8%

Various physical properties of the anamorelin monohydrochloride (orcomposition comprising anamorelin monohydrochloride) prepared accordingto the foregoing examples were evaluated and reported below in Table 2B.

TABLE 2B Particle Size Bulk KF [μm] density OVI Batch [%] D10 D50 D90[g/mL] Purity % Cl % (ppm) 1 2.0 3.0 17.0 43.0 0.29 99.9 6.0 <1000 A 2.04.2 16.0 40.6 0.29 100.0 6.0 <1000 B 2.1 4.4 17.0 40.4 0.27 100.0 5.9<1000 2 2.1 1.6 22.3 52.4 0.32 99.9 6.0 <1000 3 2.2 2.9 21.8 47.6 0.3199.9 6.0 <1000 4 2.2 4.4 24.7 52.5 0.32 99.9 6.0 <1000 * Puritydetermined by HPLC, and includes only related compounds. **OVI: OrganicVolatile Impurities.

Similarly, the amount of anamorelin monohydrochloride (or a compositioncomprising anamorelin monohydrochloride) produced, the yield of eachprocess and representative process parameters according to the presentinvention using Niro Mobile Minor (trade mark, GEA process engineeringInc.) were reported in Tables 2C and 2D.

TABLE 2C Rotary nozzle Feed Amount P Flow T inlet T outlet rate ofproduct Batch [bar] [kg/h] [° C.] [° C.] [kg/h] [kg] Yield 1 2.8 80188-192 83-87 3.3 26.0 98.6% 2 2.8 80 188-192 83-87 3.3 23.0 98.4%

TABLE 2D KF Particle Size [μm] OVI Batch [%] D10 D50 D90 Purity % Cl %(ppm) 1 2.4 6.4 16.8 33.6 99.9 6.1 173 2 2.5 7.3 19.8 38.6 100.0 6.0 notdetected

As can be seen, anamorelin monohydrochloride (or a compositioncomprising anamorelin monohydrochloride) prepared by the method ofpresent invention had desirable chloride content, reduced residualsolvent and high purity when produced under a range of spray dryingconditions.

Example 3 Stability Testing

The stability of anamorelin monohydrochloride (or composition comprisinganamorelin monohydrochloride) prepared according to the foregoingexamples was evaluated at 25° C./75% relative humidity and 40° C./75%relative humidity for one, three and six months. The purity of theanamorelin monohydrochloride (or composition comprising anamorelinmonohydrochloride) was measured using high performance liquidchromatograph (HPLC) (Hewlett-Packard HP 1100 HPLC System, AgilentTechnologies Inc.). The concentrated aqueous solution of anamorelinmonohydrochloride A of example 1 was concentrated by spray drying usingNiro QSD-3.6 (trade mark, GEA process engineering Inc.) to affordanamorelin monohydrochloride referred to as Batch A in Tables 2A and 2B)in an amorphous state. The resulting amorphous product was dissolved inacetonitrile:water (1:1) and measured under the conditions reported inTable 3A. The results are presented below in Table 3B. RRT refers to therelative retention time of the impurity versus anamorelin. In addition,the purity was converted into the amount of anamorelin free base withina sample without any other organic solvent since anamorelinmonohydrochloride (or composition comprising anamorelinmonohydrochloride) was dissolved in the solvent to be measured by HPLCcondition.

TABLE 3A Detector UV 280 nm Column Zorbax Bonus RP(4.6 mm × 250 mm, 3.5μm, Agilent) Column 55° C. temperature Mobile phase Mobile phase A: 0.1%Trifluoroacetic acid aqueous solution Mobile phase B: 0.1%Trifluoroacetic acid acetonitrile solution Gradient Time (min.) Phase A(%) Phase B (%) 0 84 16 12 74 26 26 69.5 30.5 29 69.5 30.5 41 64 36 50 793 54 7 93 54.1 84 16 62 84 16 Flow 0.85 mL/min (retention time ofanamorelin: 32 min) run duration 62 min Injection volume 10 μL

TABLE 3B month anamorelin Impurity 1 Impurity 2 Impurity 3 Impurity 4Impurity 5 Impurity 6 Impurity 7 Initial 100.0% <0.05 <0.05 <0.05 <0.05<0.05 <0.05 <0.05 25° C./60% RH 1 100.0% <0.05 <0.05 <0.05 <0.05 <0.05<0.05 <0.05 3 100.0% <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 6 100.0%<0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 40° C./75% RH 1 100.0% <0.05<0.05 <0.05 <0.05 <0.05 <0.05 <0.05 3 100.0% <0.05 <0.05 <0.05 <0.05<0.05 <0.05 <0.05 6 100.0% <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05

As can be seen, the stability of the anamorelin monohydrochloride (orcomposition comprising anamorelin monohydrochloride) prepared accordingto the present invention was nearly unchanged, and high purity wasmaintained for six months under each set of conditions.

The long-term stability of three separate batches of anamorelinmonohydrochloride (or composition comprising anamorelinmonohydrochloride) having differing chloride contents were evaluated forstability at 25° C./60% relative humidity for one, two and three years,and 40° C./75% relative humidity for one, three and six months. Theresults are presented below in Table 3C. % Increase in Table 3C wascalculated by the following formula.

% Increase=(M−I)/I×100

-   -   I: initial total impurity (%)    -   M: measured total impurity (%) at specific time (e.g., 3 months,        6 month and so forth)

TABLE 3C Initial Chloride Content (wt. %) % Increase in Total ImpuritiesFrom To at 25° C./60% RH 1 Y 2 Y 3 Y 6.2%  85% 114% 100% 6.3% 200% 340%360% 5.6%  10%  48%  29% 5.9%  0%  20%  20% % Increase in TotalImpurities From To at 40° C./75% RH 1 M 3 M 6 M 6.2% 107% 100% 171% 6.3%140% 400% 500% 5.9%  0%  21%  17%

As can be seen, the long-term stability of the anamorelinmonohydrochloride (or composition comprising anamorelinmonohydrochloride) (from 5.3% to 6.3% chloride content) preparedaccording to the present invention was nearly unchanged, and high puritywas maintained for three years under ambient storage conditions (25°C./60% RH).

Stability testing for anamorelin dihydrochloride relative to themonohydrochloride and anamorelin free base at 40° C./75% relativehumidity is reported below in Table 3D. For the anamorelindihydrochloride preparation, anamorelin free base was dissolved in ethylacetate and a molar excess of hydrochloric acid in ethyl acetate wasadded into the mixture to precipitate anamorelin dihydrochloride. Theresulting anamorelin dihydrochloride was filtered and dried (chloridecontent approximately 12.2%). HPLC Area % in Table 3D refers to theamount of converted value of anamorelin free base in samples.

As can be seen, the long-term stability of anamorelin dihydrochloridewas easy to be changed relative to the monohydrochloride. Thus, when thecontent of anamorelin dihydrochloride in the composition is increased,the composition results in less stable.

TABLE 3D Anamorelin Anamorelin Anamorelin Free Base Mono-HCl Di-HCl I.T.1M 3M I.T. 1M 3M I.T. 1M 3M HPLC Area % 99.7% 99.9% 99.7% 99.9% 99.3%99.2% 98.9% 98.2% 97.1%

Example 4 Solubility Test

A solution of standard curve was prepared to 356 μmol/L by dilutingstandard substance (anamorelin free base (quantitative value: 93.90%),86.6 mmol/L, isopropyl acetate solution) with acetonitrile. In addition,a sample solution was prepared according to the process that testcompound (about 100 mg) added into distilled water (10.00 g), thesolution was mixed for 10 minutes at 50° C. and then was placedovernight, obtained suspension was filtered by syringe with filter (0.2μm) and the filtrate (48.93 mg) was diluted with acetonitrile (10 mL). Asolution of standard curve and a sample solution (each 5 μL) weredetermined by injecting into HPLC (GULLIVER1500 HPLC system, JASCOCorporation). Since anamorelin monohydrochloride was completelydissolved in the 25% solution of anamorelin monohydrochloride (i.e.,anamorelin monohydrochloride (1 g) was dissolved in distilled water (3mL)), a solubility of anamorelin monohydrochloride was >333 mg/mL.

TABLE 4 run solvent mg/mL 1 anamorelin distilled water ( initial pH7) >333 monohydrochloride 2 Anamorelin free base distilled water(initial pH 7) 0.04

As can be seen, the solubility of the anamorelin monohydrochloride issuperior to that of anamorelin free base in distilled water,illustrating that a reduction of chloride content in anamorelinmonohydrochloride (or composition comprising anamorelinmonohydrochloride) can lead to decreased solubility.

Example 5 Physical Characterization

The amorphous form of the anamorelin monohydrochloride (or compositioncomprising anamorelin monohydrochloride) produced by spray drying wasevaluated using X-Ray powder diffraction and infrared resonance underthe following measurement conditions. The XRPD spectra and IR spectraobserved are depicted in FIGS. 1 and 2.

X-ray powder diffraction spectra Apparatus: BRUKER D8 DISCOVER withGADDS manufactured by BRUKER axs

-   -   Target: Cu,    -   Filter: None    -   Voltage: 40 kV,    -   Current: 40 mA,    -   Light exposure: 5 min.

Infrared resonance spectrum

-   -   Apparatus: FTIR-660 Plus produced by JASCO Corporation DURASCOPE        produced by SENSIR Measuring method: Potassium bromide added        into the tablet forming machine and it was pressured by        hand-press to prepare the thin film. This sample was measured as        background. Subsequently, the amorphous sample (1 mg) and        potassium bromide (100 mg) was combined and the mixture added        into the tablet forming machine to prepare the thin film and        then measured.    -   Dissolution performance: 2 cm⁻¹    -   Scanning number of time: 16 times

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains. It willbe apparent to those skilled in the art that various modifications andvariations can be made in the present invention without departing fromthe scope or spirit of the invention. Other embodiments of the inventionwill be apparent to those skilled in the art from consideration of thespecification and practice of the invention disclosed herein. It isintended that the specification and examples be considered as exemplaryonly, with a true scope and spirit of the invention being indicated bythe following claims.

1-23. (canceled) 24) A method of making a pharmaceutical dosage formcomprising: a) combining a therapeutically effective amount ofanamorelin monohydrochloride with one or more pharmaceuticallyacceptable excipients to form a mixture; b) processing said mixture intoa finished dosage form; and c) repeating steps (a) and (b) one or moreadditional times using anamorelin monohydrochloride from differentbatches, wherein the chloride content among the different batches variesby no more than 7%. 25) The method of claim 24, wherein the chloridecontent among the different batches varies by no more than 5%. 26) Themethod of claim 24 wherein the anamorelin monohydrochloride isamorphous. 27) The method of claim 24 wherein the anamorelinmonohydrochloride comprises less than 3% total impurities selected fromby-products, contaminants, and degradation products. 28) The method ofclaim 24 wherein the anamorelin monohydrochloride comprises less than 2%total impurities selected from by-products, contaminants, anddegradation products. 29) The method of claim 24 wherein the anamorelinmonohydrochloride comprises less than 1% total impurities selected fromby-products, contaminants, and degradation products. 30) The method ofclaim 24 wherein the anamorelin monohydrochloride comprises less than 5%water. 31) The method of claim 24 wherein the anamorelinmonohydrochloride comprises less than 3% water. 32) The method of claim24 wherein the anamorelin monohydrochloride comprises less than 2%water. 33) The method of claim 24 wherein the anamorelinmonohydrochloride is in an isolated state. 34) The method of claim 24wherein the finished dosage form is a tablet or capsule or pellets orgranules or powders. 35) The method of claim 24 wherein the anamorelinmonohydrochloride has a solubility in water greater than 100 mg/mL. 36)The method of claim 24 wherein the anamorelin monohydrochloride has asolubility in water greater than 333 mg/mL. 37) The method of claim 24wherein the anamorelin monohydrochloride has a stability defined by apercentage increase in impurities of no more than 114% when stored at25° C. and a relative humidity of 60% for two years. 38) The method ofclaim 24 wherein the anamorelin monohydrochloride has a stabilitydefined by a percentage increase in impurities of no more than 48% whenstored at 25° C. and a relative humidity of 60% for two years. 39) Themethod of claim 24 wherein the anamorelin monohydrochloride has achloride content of from 5.6 to 6.3%. 40) The method of claim 24 whereinthe anamorelin monohydrochloride has a residual solvent concentrationless than 5000 ppm, wherein the residual solvent concentration excludeswater. 41) The method of claim 24 wherein the anamorelinmonohydrochloride has a solubility in water greater than 333 mg/mL, anda stability defined by a percentage increase in impurities of no morethan 114% when stored at 25° C. and a relative humidity of 60% for twoyears. 42) The method of claim 24 wherein the anamorelinmonohydrochloride has a chloride content of from 5.6 to 6.3% and aresidual solvent concentration excluding water less than 5000 ppm, asolubility in water greater than 333 mg/mL, and a stability defined by apercentage increase in impurities of no more than 114% when stored at25° C. and a relative humidity of 60% for two years.